Self-Emulsifying Active Ingredient Formulation and the Use of this Formulation

ABSTRACT

The present invention relates to self-emulsifying formulations based on an active ingredient component and a formulation base with a lipid component and with a binder component and to the use of this formulation as dosage form in the life science sector. The invention also describes a process for producing self-emulsifying formulations by mixing the formulation components to form a plastic mixture and, where appropriate, to manufacture the formulations as dosage form advantageously by use of melt extrusion. The formulations spontaneously form emulsions in water or aqueous media.

This application is a continuation of U.S. patent application Ser. No.10/296,451 filed Nov. 25, 2001, which is a national stage entry ofPCT/EP01/06116 filed May 29, 2001, which claims priority from GermanPatent Application No. 10026698.3 filed May 30, 2000.

The present invention relates to self-emulsifying formulations based onan active ingredient component and a formulation base with a lipidcomponent and with a binder component; to the use of this formulation asdosage form in the life science sector; the invention also describes aprocess for producing self-emulsifying formulations by mixing theformulation components to form a plastic mixture and, where appropriate,to manufacture the formulations as dosage form; and the use of aformulation base in the application of at least one active ingredient inthe life science sector.

It is often desired to be able to employ active ingredients inemulsified form. Thus, in the pharmaceutical technology sector, activeingredients of low solubility are formulated together with selectedexcipients in order to ensure adequate absorption of the activeingredient for example in the gastrointestinal tract. These normallycomprise nonionic surfactants with quite high HILB values, e.g.Cremophor®, Tween®, etc. This applies just as much to the drugs sectoras to the crop protection sector.

For example, in WO 00/00179 oils or fats are emulsified ormicroemulsified with the addition of conventional emulsifiers, andactive ingredients of low solubility in water are then incorporated intothese emulsions or microemulsions.

Although these excipients are commonly designated chemically inert, theyare known to have disadvantages which may become evident in particularat higher dosages through local and/or systemic toxicity.

Besides local irritation, it is not possible to preclude unwanted sideeffects of these substances derived from uptake of these solubilizers byan organism.

Emulsions, for example for parenteral administration, normally useemulsifying phospholipids, in particular lecithins. However, because ofthe inadequate chemical stability of the phospholipids, these emulsionsmay be associated with considerable storage stability problems. Inaddition, the preparation of such emulsions is complicated. Thus, it maybe necessary to homogenize the phospholipids in water together withother emulsion constituents, for example lipids or lipid derivatives,under high pressure, i.e. under several 100 bar.

Besides the liquid emulsions described above, “solid” emulsions are alsoknown. These formulations are generally referred to as self-emulsifyingsystems because they dissolve in aqueous systems to form an emulsion(cf. M. O. Bachynsky et al., “Factors Affecting the Efficiency of aSelf-Emulsifying Oral Delivery System”, Drug Development and IndustrialPharmacy, 23 (8), (1997) 809-816; U.S. Pat. No. 5,858,401). Thesolubilization-promoting excipients discussed at the outset are alsomainly used in these cases, which entails the known disadvantages.Besides the low molecular weight surfactants, e.g. Tween®, which areparticularly used, self-emulsifying systems based on polymeric glyceridesurfactants are also described (A. T. M. Serajuddin, “BioavailabilityEnhancement of poorly Water-Soluble Drugs by Solid Dispersion in SurfaceActive and Self-Emulsifying Vehicles”, Bulletin Technique Gattefossé,No. 90, (1997), pp. 43-50). These polymeric glycerides may act assurfactant because of their high HLB values (e.g. Gelucire® 44/14 withan HLB of 14). Because of their semisolid consistency, many of theseformulations must be packed into gelatin capsules. This applies inparticular to the use of the usually low-melting glyceride surfactants.

The object on which the present invention is based, of providingself-emulsifying dosage forms, is surprisingly achieved by formulationswhose formulation base comprises a lipid component and a bindercomponent.

The present invention therefore relates to self-emulsifying formulationsbased on

-   -   at least one active ingredient    -   and a formulation base with    -   ii) a lipid component;    -   iii) a binder component; and    -   iv) where appropriate other excipients.

The term “formulation” means in the framework of the present invention amixture composed of components i), ii), iii) and, where appropriate,iv).

Active ingredients mean for the purpose of the invention all substanceswith a physiological effect. They are, in particular, activepharmaceutical ingredients (for humans and animals in the human andveterinary medical sectors), active ingredients for plant treatment,insecticides, active ingredients for human and animal food, fragrances,flavorings and perfumed oils. The amount of active ingredient per doseunit and the concentration may vary within wide limits depending on theactivity and the release rate. A condition is that they suffice toachieve the desired effect.

Active ingredients for the purpose of the invention also includevitamins and minerals. The vitamins include the vitamins of the A group,the B group, which are meant besides B₁, B₂, B₆ and B₁₂ and nicotinicacid and nicotinamide to include also compounds with vitamin Bproperties such as adenine, choline, pantothenic acid, biotin, adenylicacid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoicacid, myo-inositol and lipoic acid, and vitamin C, vitamins of the Dgroup, E group, F group, H group, I and J groups, K group and P group.Active ingredients for the purpose of the invention also includetherapeutic peptides. Plant treatment agents include, for example,vinclozolin, epoxiconazole and quinmerac.

Active pharmaceutical ingredients include, for example:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam,alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride,aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin,ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkoniumhydrochloride, benzocaine,benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol,bromazepam, bromhexine, bromocriptine, budesonide, bufexamac,buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine,carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazolin,cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline,chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone,choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride,cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam,clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid,cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol,dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxocyclin, enalapril, ephedrine, epinephrine, ergocalciferol,ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide,Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol,fentanyl, flavinmononucleotide, fluconazole, flunarizine, fluorouracil,fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil,gentamicin, Gingko biloba, glibenclamide, glipizide, clozapine,Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin,hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone,hydromorphone, ipratropion-hydroxide, ibuprofen, imipenem, indomethacin,iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate,isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol,lactulose, lecithin, levocarnitine, levodopa, levoglutamide,levonorgestrel, levothyroxine, lidocaine, lipase, imipramine,lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone,menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide,metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol,morphine, multivitamin mixtures or combinations and mineral salts,N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine,nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine,nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone,norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole,ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol,penicillin G, penicillin V, pentoxifylline, phenobarbital,phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin,piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam,prazosin, prednisolone, prednisone, propafenone, propranolol,proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril,ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside,saccharin, salbutamol, salcatonin, salicylic acid, simvastatin,somatropin, sotalol, spironolactone, sucralfate, sulbactam,sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur,teprenone, terazosin, terbutaline, terfenadine, tetracycline,theophylline, thiamine, ticlopidine, timolol, tranexamic acid,tretinoin, triamcinolone-acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E,folinic acid, zidovudine.

The active ingredients which can be used according to the invention alsoinclude a large number of essential oils (aetheroleum), such as angelicaoil (angelicae aetheroleum), anise oil (anisi aetheroleum), arnica oil(arnicae aetheroleum), aurantii aetheroleum, valerian oil (valerianaeaetheroleum), basilici aetheroleum, bergamot oil (bergamottaeaetheroleum), savory oil, bucco aetheroleum, camphor (camphora),cardamomi aetheroleum, cassia oil, chenopodium oil (chenopodiiaetheroleum), chrysanthemum oil (pyrethri aetheroleum), cinaeaetheroleum, citronella oil, lemon oil (limonis aetheroleum), citrus oil(citri aetheroleum), costus oil, curcuma oil (curcumae aetheroleum),carlina oil (carlinae aetheroleum), elemi oil, tarragon oil, eucalyptusoil (eucalypti aetheroleum), fennel oil (foeniculi aetheroleum), pineneedle oil (piceae aetheroleum), pine oil, filicis aetheroleum, galbanumoil, gaultheriae aetheroleum, geranium oil, guaiac wood oil (guaiaciaetheroleum), hazelwort oil (asari aetheroleum), iris oil (iridisaetheroleum), hypericum oil (hyperici aetheroleum), calamus oil,camomile oil (e.g. chamomillae romanae aetheroleum; matricariaeaetheroleum), fir needle oil (pini aetheroleum), garlic oil (alliisativi aetheroleum), coriander oil (coriandri aetheroleum), carraway oil(carvi aetheroleum), lauri aetheroleum, lavender oil (lavandulaeaetheroleum), lemon grass oil, lovage oil (levistici aetheroleum), bayoil, lupuli strobuli aetheroleum, mace oil, marjoram oil (majoranaeaetheroleum), mandarine oil, melissa oil (melissae aetheroleum;calaminthae aetheroleum), menthol (mentholum), millefolii aetheroleum,mint oil (menthae arvensis aetheroleum), clary oil, nutmeg oil(mristicae aetheroleum), spikenard oil (e.g. from Nardostachysjatamansi), clove oil (caryophylli aetheroleum), neroli oil, niaouli,olibanum oil, ononidis aetheroleum, opopranax oil, orange oil, oreganooil, orthosiphon oil, patchouli oil, parsley oil (petroselinumaetheroleum), petit-grain oil, peppermint oil (menthae piperitaeaetheroleum), tansy oil (tanaceti aetheroleum), rosewood oil, rose oil,rosemary oil (rosmarini aetheroleum), rue oil (rutae aetheroleum),sabinae aetheroleum, saffron oil (croci aetheroleum), sage oil (salviaeaetheroleum), sandalwood oil (santali aetheroleum), sassafras oil(sassafras aetheroleum), celery oil (apii aetheroleum), mustard oil(senapsis aetheroleum), serphylli aetheroleum, immortelle oil (e.g. fromHelichrysum italicum), fir oil, teatree oil, terpentine oil(terebinthinae aetheroleum), thyme oil (thymi aetheroleum), juniper oil(juniperi aetheroleum), frankincense oil, hyssop oil (e.g. Hyssopusofficinalis var. decumbens), cedar wood oil, cinnamon oil (cinnamomiaetheroleum), cypress oil.

Some of the aforementioned essential oils can also be used asinsecticides, e.g. chrysanthemum oil and calamus oil, or as repellents,e.g. cassia oil, camphor, terpentine oil, citronella oil, cinnamon oiland clove oil.

The essential oils are usually mixtures of substances. Components of themixture which should be particularly mentioned are terpene compounds,e.g monoterpenes, sesquiterpenes, and biterpenes and triterpenes,phenylpropane derivatives, simple phenols and their ethers,phenoicarboxylic acids, straight-chain hydrocarbons and theirderivatives, short-chain acids, sulfur-containing compounds, e.g.mustard oils, and nitrogen-containing substances, e.g. indolederivatives and anthranilic esters.

In the true sense, the term “essential oil” means mixtures of substanceswhich are obtainable from plant raw materials by steam distillation.Oils of this type can be obtained, depending on the amount and nature ofthe oil and depending on the plant raw material employed to obtain it,by oil extraction processes (enfleurage process), solvent extraction,pressing processes and other mechanical processes, and distillationprocesses, which include steam distillation. The oils obtained in thisway can be subjected to further purification. This is advantageous inparticular with steam-distilled oils and particularly expedient with aview to the pharmaceutical or cosmetic applications.

Active component i) in the formulations of the invention contains atleast one active ingredient, in particular one of those aforementioned,and it may contain other active ingredients, to be selected inparticular from those aforementioned, of the same or a different type.

A special type of active ingredient within the framework of the presentinvention is to be included, because of its fat-like nature, among thelipids, where appropriate also as lipid derivative or lipid-containingmixture. Active ingredients of this type are referred to hereinafter aslipid-like active ingredients. Statements concerning lipids also referto such lipid-like active ingredients. The lipid-like active ingredientswhich can be used according to the invention are, in particular, oilsand, especially, the aforementioned essential oils. This type of activeingredient may form a part or the entirety both of active ingredientcomponent i) and of lipid component ii). In a particular aspect,therefore, the present invention relates to self-emulsifyingformulations based on

-   -   i′) at least one lipid-like active ingredient and, where        appropriate, other active ingredients    -   and a formulation base with        -   ii′) where appropriate another lipid component content;    -   iii) a binder component; and    -   iv) where appropriate other excipients.

Accordingly, component i′) comprises the active ingredient component i)and at least part of the lipid component ii); and component ii′)comprises the part of lipid component ii) which is not comprised by i′).In a specific embodiment of this aspect, component i′) comprises activeingredient component i) and lipid component ii), with the consequencethat component ii′) is not present, The component i′) comprises at leastone lipid-like active ingredient, i.e, it may also comprise two or moreof these lipid-like active ingredients or else one or more other activeingredients. In another specific embodiment of this aspect, componenti′) consists of at least one lipid-like active ingredient.

Accordingly, the term “lipid component” refers—unless otherwiseindicated—generally to component ii) and specifically, for example, tothe lipid content of component i′), where appropriate in combinationwith component ii′).

The formulations of the invention are particularly advantageous forthose active ingredients which profit from the solubilizing property ofthe emulsions resulting when the formulations are dissolved in aqueousmedia. These are, in particular, active ingredients of low solubility,in particular those for which at least 100, in particular at least 1 000parts, and preferably at least 10 000 parts of water are necessary todissolve one part of active ingredient, but also active ingredientswhich are freely soluble in water but display only inadequate effectswith certain mode of administration.

The active ingredient component i) usually constitutes 0.1 to 50% byweight, preferably 1 to 30% by weight, and in particular 5 to 20% byweight, of the formulation. Data in % by weight relate, unless otherwiseindicated, to the total weight of the formulation.

The formulation base of formulations of the invention comprisesexcipients, namely in one embodiment at least one lipid, at least onebinder and, where appropriate, other excipients and, in anotherembodiment in which the active ingredient component comprises at leastone lipid-like active ingredient, comprises at least one binder and,where appropriate, other lipids and/or other excipients.

The lipid component of solid formulations of the invention comprises atleast one lipid, which is intended to refer also to lipid derivativesand lipid-containing mixtures.

The term lipid is a collective designation for fats and fat-likesubstances. The similarity to fats is defined in particular by thesolubility characteristics. Accordingly, fat-like substances such asfats themselves are, for example, practically insoluble in water.Substances are insoluble in water in the sense of the inventionespecially when at least 1 000 to 10 000 parts, and preferably at least10 000 parts of water are necessary to dissolve one part of substance.They are also referred to as lipophilic or hydrophobic.

In one embodiment of the present invention, preferred lipids are thosewhich an organism can assimilate, that is to say, for example, can takeup and, where appropriate, metabolize. In this sense, those lipids andlipid derivatives which can be taken up via the gastrointestinal tractimplement a particular embodiment of the present invention, inparticular within the framework of pharmaceutical applications. Naturallipids and derivatives of natural lipids, which may be of vegetable oranimal origin, are preferred.

Particularly within the framework of pharmaceutical applications, atleast one lipid of the lipid component is preferably selected fromendogeneous lipids. The endogeneous lipids include in particular lipidswhich are based on fatty acids with an even number of carbon atoms, inparticular corresponding glycerides and fatty acids or derivativesthereof.

The term fatty acid refers to a group of aliphatic saturated orunsaturated carboxylic acids. The chains are usually unbranched and have6 to 30, preferably 8 to 22, and in particular 8 to 18, carbon atoms.The saturated fatty acids include, for example, caproic acid, enanthicacid, caprylic acid, pelargonic acid, capric acid, undecanoic acid,lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid,palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidicacid, behenic acid, lignoceric acid, cerotic acid and melissic acid. Theunsaturated fatty acids may be unsaturated one or more times, inparticular unsaturated once, twice, three times, four times, five timesor six times. Examples of singly unsaturated fatty acids includepalmitoleic acid, oleic acid and erucic acid, of doubly unsaturatedfatty acids include sorbic acid and linoleic acid, of triply unsaturatedfatty acids include linolenic acid and eleostearic acid, of quadruplyunsaturated fatty acids include arachidonic acid, of quintuplyunsaturated fatty acids include clupanodonic acid, and of sextuplyunsaturated fatty acids include docosahexaenoic acid.

Singly or multiply unsaturated fatty acids are preferred, especiallyoleic acid, palmitoleic acid, erucic acid, linoleic acid, linolenicacid.

The term glycerides refers to esters of glycerol. Depending on thenumber of ester groups, reference is made to mono-, di- andtriglycerides. The acid residue in a monoglyceride may be at position 1or 2 and the acid residues of di- and triglycerides may be identical ordifferent and be distributed in every conceiveable way over the threepossible positions of glycerol. The acid residues are preferably thefatty acids described above. Examples of monoglycerides include glycerolmonobehenate, glycerol monocaprate, glycerol monococoate, glycerolmonoerucate, glycerol monoisostearate, glycerol monolanolate, glycerolmonolaurate, glycerol monolinoleate, glycerol monomyristate, glycerolmonooleate, glycerol monopalmitate, glycerol monoricinoleate, glycerolmonostearate, of the diglycerides include glycerol dicaprylate, glyceroldilaurate, glycerol dimyristate, glycerol dioleate, glycerol dipalmitateand glycerol distearate, of the triglycerides include glyceroltricaprylate, glycerol trilaurate, glycerol trimyristate, glyceroltrioctanoate, glycerol trioleate, glycerol triricinoleate and glyceroltristearate.

Preference is given to mono-, di- and triglycerides with unsaturatedfatty acid residues, in particular the fatty acid residues which canpreferably be used according to the invention, especially glycerolmonooleate, glycerol dioleate, glycerol trioleate.

The lipid component of formulations of the invention preferablycomprises at least one of the lipids described above or a mixture of atleast two of the lipids described above, and it may contain other lipidsof this type and also of other types.

In one embodiment of the present invention, the lipid component consistsof one of the lipids described above.

In another embodiment of the present invention, the lipid componentconsists of a lipid mixture of at least two of the lipids describedabove, in particular of a fatty acid mixture, a glyceride mixture or afatty acid/glyceride mixture.

The derivatives of natural lipids, which may be of vegetable or animalorigin, include in particular those natural lipids which have beenchemically and/or physically treated. A suitable chemical treatment is,for example, hydrogenation of unsaturated fatty acids or fatty acidresidues in glycerides. A suitable physical treatment is, for example,fractionation of natural lipid mxtures.

The lipids which can be used according to the invention also includelipid-containing natural substance extracts which, besides lipid, mayalso contain other constituents. Mention should be made here inparticular of the lipids and lipid mixtures listed in relevantpharmacopoeias, and derivatives thereof, such as vegetable oils oranimal fats, e.g. olive oil, castor oil, sesame oil, peanut oil, almondoil, linseed oil, cocoa butter, sunflower oil, medium chain-lengthtriglycerides (triglycerida mediocatenalia), calcium behenate, glycerolmonostearate, medium chain-length partial glycerides (partialglyceridamediocatenalia), longer-chain partial glycerides (partialglyceridalongicatenalia), which may also, where appropriate, be hydrogenated orrefined, such as hydrogenated castor oil or refined castor oil. Onceagain, lipids with a content of unsaturated fatty acids or fatty acidresidues are preferred.

In a particular embodiment of the present invention, at least part ofthe lipid component is formed by at least one lipid-like activeingredient. Reference is made mutatis mutandis to the above statementsconcerning lipid-like active ingredients. A specific embodimentcomprises formulations of the invention with a lipid component whichconsists of at least one lipid-like active ingredient, in particular theaforementioned oils and especially, the essential oils.

In a particular embodiment, lipid component i) or the lipid content ofcomponent i′), where appropriate in combination with component ii′), hasan HLB not exceeding 12, preferably not exceeding 8 and, in particular,not exceeding 5. The HLB system (hydrophilic lipophilic balance system)assigns numerical values to surface-active substances; the HLB values oflipophilic substances are low, and those of hydrophilic ones are higher(Fiedler, H. B., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik, undangrenzende Gebiete, 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag(1996)). In particular, lipid component ii) or the lipid content ofcomponent i′), where appropriate in combination with component ii′), isinsoluble or of only low solubility in water. Accordingly, thisembodiment can be implemented in particular with the aforementionedfatty acids and glycerides or oils and especially essential oils.

In another preferred embodiment, lipid component ii) or the lipidcontent of component i′), where appropriate in combination withcomponent ii′), has a melting point not exceeding 50° C., preferably notexceeding 40° C. and, in particular, less than 30° C. Accordingly, thisembodiment can be implemented in particular with fatty acids such astridecanoic acid, lauric acid, elaeostearic acid, preferably undecanoicacid, capric acid, erucic acid, in particular pelargonic acid, caprylicacid, enanthic acid, caproic acid, isostearic acid, oleic, acid,palmitoleic acid, linoleic acid, linolenic acid, arachidonic acid,clupanodonic acid and docosahexaenoic acid, and glycerides such asglycerol monolaurate, glycerol monolinoeate, glycerol monooleate,glycerol monopalmitate, glycerol monoricinoleate, glycerol dioleate,glycerol trioleate and glycerol triricinoleate, and with theaforementioned essential oils.

It is particularly preferred for at least part of lipid component ii) orof the lipid content of component i′), where appropriate in combinationwith component ii′), and at least part of the binder component to form amolecular dispersion in the formulations of the invention. If the lipidcontent is greater than the binder content, there is said to be amolecular dispersion of the binder in the lipid. The lipid content ispreferably less than the binder content, in which case there is said tobe a molecular dispersion of the lipid in the binder.

The term “molecular dispersion” is known to the skilled worker andessentially describes systems in which a substance, in the present caseat least part and preferably the predominant part of the lipid or bindercomponent, is homogeneously dispersed in a solvent. In such cases, thesolvent usually forms a matrix which, according to the invention, isformed by the binder or lipid component or at least by a predominantpart of the binder or lipid component. The content of lipid crystals ina formulation of the invention is usually below 12% and, in particular,below 5%. Statements concerning contents of crystals are based on thetotal amount of the respective component.

In a particular embodiment, molecular dispersion systems are solid, inwhich case they are referred to as solid solutions.

A formulation of the invention which is essentially free of lipidcrystals represents a particular embodiment of the present invention.This state corresponds to the maximum possible homogenization of thelipid or binder in the matrix. There are no interfaces in the moleculardispersion system.

In another particular embodiment, at least part of the active ingredientcomponent is in the form of a molecular dispersion. The content ofactive ingredient crystals in a formulation of the invention is usuallyless than 12% and, in particular, less than 5%. These formulationsinclude, in particular, those which are essentially free of activeingredient crystals. This state corresponds to the maximum possiblehomogenization of the active ingredient in the formulation base.

Formulations of the invention which are essentially free of lipid andactive ingredient crystals and, in particular, those in which there areessentially no crystalline contents of any constituent (essentiallyamorphous or crystal-free formulations) represent another particularembodiment of the present invention. This state corresponds to themaximum possible homogenization of the formulation components. There areno interfaces in a formulation which is a molecular dispersion.

Known analytical methods can be used to investigate the state of suchmolecular dispersions, in particular solid solutions, for exampledifferential scanning calorimetry (DSC) or wide angle X-ray scatteringmeasurements (WAXS measurements). The DSC analytical measurement of amolecular dispersion lacks the melting peak which occurs with thecrystalline pure substance and is usually endothermic. Anotherpossibility for identifying a molecular dispersion is the reduction inintensity and/or absence of typical X-ray diffraction signals in theWAXS analysis.

The content of the lipid component in the formulation is usually from 6to 60% by weight, preferably 11 to 40% by weight, and in particular 16to 25% by weight.

One criterion for establishing the optimal amount of lipid is thehomogeneity of the formulation of the invention in the melt. Especiallyin relation to the upper limit, a homogeneous incorporation of the lipidinto the melt without phase separation ought to be ensured.

In a particular embodiment of the present invention, the content oflipid component ii) or of the lipid content of component i′), whereappropriate in combination with component ii′), based on the bindercomponent, is not more than 40% by weight, preferably not more than 30%by weight, and in particular not more than 25% by weight.

The binder component of the formulations of the invention can also beunderstood as binder which at least partly forms a binder matrix, inparticular a polymer matrix. Binders for the purpose of the inventionare solid, meltable solvents. The binder matrix serves especially totake up, and in particular to dissolve, at least part of lipid componenti) or of the lipid content of component i′), where appropriate incombination with component ii′). This preferably leads to the formationof molecular dispersions. In this regard, reference is made to the abovestatements in connection with the lipid component.

The binder component is preferably at least partly soluble or swellablein aqueous media, expediently under the conditions of use, that is tosay in particular physiological conditions.

Aqueous media include, within the framework of the present description,water and mixtures of water and other components which contain at least50% by weight, preferably at least 70% by weight, and in particular atleast 90% by weight, of water. Aqueous media include in particular bodyfluids such as fluids in the digestive tract, e.g. gastric juice andintestinal juices, saliva, urine, feces fluid, wound discharge,effusions, amniotic fluid, puncture fluids, lymph and blood; beveragesbased on water, such as tea, coffee, soft drinks or babyfood, food forparenteral nutrition, juices, syrups, water used for various purposes,for example in animal feeding and for watering plants, and forcontrolling pests, water for use in cleaning processes, e.g. forlaundering or dishwashing, bath water, aqueous vehicles for use informulations in the drugs, cosmetics or plant treatment sector, e.g.vehicles which can be administered parenterally, ointment, cream, pasteor gel bases, water or aqueous media for use in aromatherapies or forinhalation.

Swelling means essentially a process in which the volume and/or shape ofa solid body, for example a solid formulation of the invention, changeon exposure to liquids, vapors and gases. Swellable or soluble appliesin particular to hydrophilic polymers able to accumulate water at leaston the surface and/or take up water between the polymer chains, mainlyby absorption. Limited swelling usually results in gel formation, whichis why polymers capable of limited swelling and usable according to theinvention can be selected from the polymers commonly known as gelformers. Unlimited swelling usually leads to the formation of solutionsor colloidal solutions, which is why polymers capable of unlimitedswelling and usable according to the invention can be selected from thepolymers which form at least colloidal solutions in the respectiveaqueous medium. It must be taken into account, for pharmaceuticalapplications and, in particular, in relation to body fluids, for examplethose of the gastrointestinal tract, that there may be local differencesin the physiological conditions, especially the pH. If it is preferred,for example, for the active ingredient to be absorbed mainly in theduodenum, it may be advantageous for the binder component to beswellable under the conditions prevailing in the duodenum. Inparticular, it may be advantageous for only slight or preferablyessentially no swelling to take place in the preceding sections of thegastrointestinal tract, especially in the stomach. However, it may beremarked at this point that such behavior of formulations of theinvention after administration can also be ensured with other means, inthe case described above for example with coatings resistant to gastricjuice or multilayer formulations in which the innermost layerscontaining active ingredient are exposed to swelling or dissolving onlyat the required site.

In a particular embodiment, the binder component iii) forms no micellesunder the conditions of use of the formulation. No CMC (criticalmicellar concentration) is reached.

Binder components technically advantageous for the process are thosewhich are melt-processable.

It is preferred for at least one binder of the binder component to beselected from:

synthetic polymers such as polyvinyllactams, in particularpolyvinylpyrrolidone (PVP); copolymers of vinyllactams such asN-vinylpyrrolidone, N-vinylpiperidone and N-vinyl-ε-caprolactam, butespecially N-vinylpyrrolidone, with (meth)acrylic acid and/or(meth)acrylic esters, such as long-chain (meth)acrylates, e.g. stearyl(meth)acrylate, dialkylaminoalkyl (meth)acrylates, which may bequaternized, and maleic anhydride, vinyl esters, especially vinylacetate, vinylformamide, vinylsulfonic acid or quaternizedvinylimidazole; copolymers of vinyl acetate and crotonic acid; partiallyhydrolyzed polyvinyl acetate; polyvinyl alcohol; (meth)acrylic resinssuch as poly(hydroxyalkyl (meth)acrylates), poly(meth)acrylates,acrylate copolymers, e.g. from alkyl acrylates with (meth)acrylic acid,and copolymers of dimethylaminoethyl acrylates and methacrylic esters(e.g. Eudragit types); polyalkylene glycols such as polypropyleneglycols and polyethylene glycols, preferably with molecular weightsabove 1 000, particularly preferably above 2 000 and very particularlypreferably above 4 000 (e.g. polyethylene glycol 6 000); polyalkyleneoxides such as polypropylene oxides and, in particular polyethyleneoxides, preferably of high molecular weight, especially with weightaverage molecular weights of more than 100 000; copolymers of methylmethacrylate and acrylic acid; polyacrylamides, polyvinylformamide(where appropriate partially or completely hydrolyzed);

modified natural polymers, e.g. modified starches and modifiedcelluloses, such as cellulose esters and, preferably cellulose ethers,e.g. methylcellulose and ethylcellulose, hydroxyalkylcelluloses,

in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses,

in particular hydroxypropylmethylcellulose orhydroxypropylethylcellulose, cellulose phthalates, in particularcellulose acetate phthalate and hydroxypropylmethylcellulose phthalate,starch degradation products, in particular starch saccharificationproducts, such as maltodextrin;

natural or predominantly natural polymers such as gelatin,polyhydroxyalkanoates, e.g. polyhydroxybutyric acid and polylactic acid,polyamnino acids, e.g. polylysine, polyasparagine, polydioxanes andpolypeptides, and mannans, especially galactomannans; and

nonpolymeric binders such as polyols, for example those described in WO98/22094 and EP 0 435 450, especially sugar alcohols such as maltitol,mannitol, sorbitol, cellobiitol, lactitol, xylitol, erythritol andisomalt (Palatinit).

In one embodiment of the present invention, at least one binder of thebinder component is selected from the modified natural and, inparticular, the synthetic polymers. In another embodiment of the presentinvention, at least one binder of the binder component is selected fromthe sugar alcohols or the starch saccharification products.

It is particularly preferred for at least one polymer of the bindercomponent to be selected from polyvinylpyrrolidones,vinylpyrrolidone/vinyl acetate copolymers, hydroxyalkylcelluloses,

hydroxyalkylalkylcelluloses, cellulose phthalates, polyalkylene glycols,(meth)acrylic resins: for example the polyvinylpyrrolidone having theproprietary name Kollidon® and weight average molecular weights of about2 000 to about 1.5×10⁶, for example the polyvinylpyrrolidone having theproprietary name Kollidon® 17 PF and a weight average molecular weightof about 7 000 to about 11 000; vinylpyrrolidone/vinyl acetatecopolymers, in particular with a vinylpyrrolidone:vinyl acetate ratio offrom about 30:70 to about 70:30, for example the product having theproprietary name Kollidon® VA 64 and a vinylpyrrolidone:vinyl acetateratio of about 60:40; hydroxyalkylcelluloses with 1 to 3 carbon atoms inthe alkyl moiety, in particular hydroxypropylcellulose, for example thehydroxypropylcellulose having the proprietary name Klucel®,hydroxyalkylalkylcelluloses with 1 to 3 carbon atoms in the alkylmoieties; in particular hydroxypropylmethylcellulose, for example themethylcellulose and methylcellulose derivative mixtures having theproprietaty name Methocel® and containing ethyl, hydroxyethyl,hydroxypropyl and carboxymethyl ether groups, cellulose phthalates,especially hydroxypropylmethylcellulose phthalate, polyalkylene glycolswith 2 and/or 3 carbon atoms in the alkylene moiety, especiallypolyethylene glycols, for example the polyethylene glycols having theproprietary name Lutrol® and weight average molecular weights of from 2000 up to about 20 000, and polypropylene glycols, copolymers based ondimethylaminoethyl methacrylate and methacrylic esters such as methylmethacrylate and butyl methacrylate, for example the acrylic resinshaving the proprietary name Eudragit® E and based on dimethylaminoethylmethacrylate, methyl and butyl (meth)acrylate with weight averagemolecular weights of about 150 000, copolymers with anioniccharacteristics based on methacrylic acid and methyl methacrylate, forexample the acrylic resins having the proprietary names Eudragit® L andS and with weight average molecular weights of about 250 000 and 135000, respectively.

Very particular preference is given to the aforementionedpolyvinylpyrrolidones and cellulose derivatives, especially Kollidon® VA64 and low molecular weight hydroxypropylcellulose, e.g. Klucel® EF withweight average molecular weights of about 45 000 to about 70 000 orabout 80 000, and hydroxypropylmethylcellulose, e.g. Methocel® E3, E5and E7.

The binder component of formulations of the invention preferablycomprises at least one of the binders described above. It may containother binders of these types and/or other types. The properties of theformulation of the invention can be altered by nature of the binderchosen or the admixture of different binders. In particular, it ispossible in this way to control the release of active ingredient.

In one embodiment of the present invention, the binder componentconsists of one of the binders described above. In another embodiment ofthe present invention, the binder component consists of a mixture of atleast two of the binders described above.

In a specific embodiment of the present invention, the binder componentcomprises at least one sugar alcohol, which is preferably selected frommaltitol, xylitol and isomalt, and/or one or more starchsaccharification product(s), in particular maltodextrin, whereappropriate in combination with one or more hydrophilic polymers, whichare preferably selected from the abovementioned modified natural andsynthetic polymers, e.g. polyvinylpyrrolidones, vinylpyrrolidonecopolymers, especially with vinyl acetate, or cellulose derivatives, inparticular hydroxypropylcelluloses, hydroxypropylmethylcelluloses ormethylcelluloses, or polyethylene glycols. These constituents of thisbinder component are preferably present in the following ratios ofamounts:

iii1) 5 to 90% by weight, preferably 10 to 50% by weight, and inparticular 15 to 30% by weight, of at least one sugar alcohol and/or atleast one starch saccharification product;

-   -   iii2) 10 to 95% by weight, preferably 50 to 90% by weight, and        in particular 70 to 85% by weight, of at least one hydrophilic        polymer;    -   iii3) where appropriate, at least one of the polymers described        above;    -   where the total of the contents of iii1), iii2), and iii3)        comprises 100% by weight of the binder component.

Binders which are advantageous for use as polymeric binder are thosewhich have a K value (according to H. Fikentscher, Cellulose-Chemie 13(1932), pp. 58-64 and 71-74) in the range between 10 and 100, inparticular between 15 and 80.

The content of the binder component in the formulation of the inventionis usually 20 to 93.9% by weight, preferably 30 to 90% by weight and, inparticular, 40 to 80% by weight.

In the pharmaceutical formulation sector, the content of the bindercomponent in the formulation of the invention is, in particular, 20 to80% by weight, preferably 30 to 60% by weight and, in particular, 40 to50% by weight.

Formulations of the invention may, besides lipid component ii) or thelipid content of component i′), where appropriate in combination withcomponent ii′), and binder component iii), contain further excipients,e.g. pharmaceutically and cosmetically acceptable excipients (excipientcomponent iv). Such excipients may facilitate production of theformulation and/or modulate its properties. The nature and amount areadvantageously chosen so that they do not impair development of thespecial properties of the formulations of the invention and of amolecular dispersion, in particular of a solid solution which is presentwhere appropriate, or contribute to destabilizing this system.

Excipients are, for example, conventional pharmaceutical excipients, thetotal amount of which may be up to 100% by weight based on the bindercomponent, for example,

fillers such as the abovementioned sugar alcohols, e.g. mannitol,sorbitol, xylitol and isomalt (cf. DE 195 36 394), talc, sucrose,lactose, cereal or corn starch, potato flour, where present inparticular in a concentration of 0.02 to 50, preferably 0.20 to 20, % byweight based on the total weight of the mixture;

lubricants, glidants and mold release agents such as magnesium, aluminumand calcium stearates, talc and silicones, and animal or vegetable fats,especially in hydrogenated form and those which are solid at roomtemperature. These fats preferably have a melting point of 30° C. orabove. Technically preferred in relation to the melt extrusion processare—as described in DE 197 31 277—triglycerides of C₁₂, C₁₄, C₁₆ and C₁₈fatty acids or—to improve the processing properties—lecithin, asdescribed in connection with the extrusion of an isomalt-containingpolymer/active ingredient melt in DE 195 36 394. It is also possible touse waxes such as carnauba wax. These fats and waxes may advantageouslybe admixed alone or together with mono- and/or diglycerides orphosphatides, in particular lecithin. The mono- and diglycerides arepreferably derived from the abovementioned fatty acid types. The lipidswhich are present according to the invention normally carry out thefunction of these excipients, so that only small amounts and,advantageously, no lubricants, glidants and mold release agents areadded as excipients to the formulation. Where present, the total amountof excipients in the form of lubricants and mold release agents ispreferably 0.1 to 10% by weight and, in particular, 0.1 to 1% by weight,based on the total weight of the mixture;

flow regulators, e.g. diatomaceous earths, especially the high-puritysilicon dioxides having the proprietary name Aerosil®, where present inparticular in an amount of 0.1 to 5% by weight based on the total weightof the mixture;

dyes such as azo dyes, organic or inorganic pigments or dyes of naturalorigin, with preference being given to inorganic pigments where presentin a concentration of 0.001 to 10, preferably 0.5 to 3% by weight basedon the total weight of the mixture;

stabilizers such as antioxidants, light stabilizers, hydroperoxidedestroyers, radical scavengers, stabilizers against microbial attack;

plasticizers, especially those described below.

It is also possible to add wetting agents, preservatives, disintegrants,adsorbents and mold release agents, and surfactants, especially anionicand nonionic, such as, for example, soaps and soap-like surfactants,alkyl sulfates and alkylsulfonates, salts of bile acids, alkoxylatedfatty alcohols, alkoxylated alkylphenols, alkoxylated fatty acids andfatty acid glycerol esters, which may be alkoxylated, and solubilizerssuch as Cremophor (polyethoxylated castor oil), Gelucire, vitamin E TPGSand Tween (ethoxylated sorbitan fatty acid esters) (cf., for example, H.Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart1978). Since the formulations of the invention form emulsions on contactwith water or aqueous solvents, it is possible to keep the addition ofsurface-active excipient, in particular substances with high HLB values,especially of more than 8, 10 and, in particular, above 15, low, usuallyin amounts of less than 1% by weight. It is possible and advantageous todispense with such an addition.

Excipients for the purpose of the invention also mean substances forproducing a solid solution with the active ingredient. Examples of theseexcipients are pentaerythritol and pentaerythritol tetraacetate, urea,phosphatides such as lecithin, and sugar alcohols such as xylitol andmannitol, citric and succinic acids, bile acids, stearins and others asindicated, for example, by J. L. Ford, Pharm, Acta Helv. 61, (1986), pp.69-88.

Also regarded as excipients are additions of acids and bases to controlthe solubility of an active ingredient (see, for example, K. Thoma etal., Pharm. Ind. 51, (1989), pp. 98-101).

It is also possible to add excipients such as masking flavors andodor-masking agents, in particular sweeteners and odorants.

An embodiment of this type is based on expert knowledge as described,for example, in Fiedler, H. B., Lexikon der Hilfsstoffe für Pharmazie,Kosmetik, und angrenzende Gebiete, 4th edition, Aulendorf:ECV-Editio-Cantor-Verlag (1996).

Excipients in the sense of the invention are also vehicles specific forthe dosage form, i.e. appropriate for a particular dosage form, inparticular oral and, especially, tablets and capsules, also low-meltingor liquid excipients such as polyalkylene glycols of low molecularweight, in particular polyethylene glycol and/or polypropylene glycolwith weight average molecular weights of less than 1 000, water orsuitable aqueous systems.

The excipient component in formulations of the invention preferablycomprises at least one of the other excipients described above. It maycomprise other excipients of these types and/or other types.

One embodiment of the present invention comprises formulation bases withexcipient component. In this case, the content of other excipients inthe formulations of the invention can be up to 30% by weight, preferably1 to 20% by weight and, in particular, 6 to 15% by weight.

A particular embodiment of the present invention comprises formulationswhich comprise

-   -   i) at least one active ingredient, preferably an active        pharmaceutical ingredient;    -   ii) at least one unsaturated fatty acid, which is preferably        selected from oleic acid, linoleic acid and/or linolenic acid,        or corresponding mono- or diglycerides;    -   at least one binder which is selected from        polyvinylpyrrolidones, vinylpyrrolidone copolymers, in        particular with vinyl acetate, or cellulose derivatives, in        particular hydroxypropylcelluloses and        hydroxypropylmethylcelluloses; and    -   iv) where appropriate other excipients, for example a flow        regulator.

Another particular embodiment of the present invention comprisesformulations which comprise

-   -   i′) at least one lipid-like active ingredient, preferably an oil        and, in particular, an essential oil;    -   ii′) where appropriate one or more other lipids;    -   iii) at least one sugar alcohol, in particular maltitol and/or        isomalt, and at least one starch saccharification product, in        particular maltodextrin; and    -   iv) where appropriate other excipients.

Formulations of this type may, in particular, also comprise otherbinders such as the abovementioned modified natural and syntheticpolymers, e.g. polyvinylpyrrolidones, vinylpyrrolidone copolymers, inparticular with vinyl acetate, or cellulose derivatives, in particularhydroxypropylcelluloses, hydroxypropylmethylcelluloses ormethylcellulose, or polyethylene glycols.

The formulations of the invention preferably contain less than 5% byweight and, in particular, less than 1% by weight of water. A particularembodiment is represented by essentially anhydrous formulations.

The formulations of the invention preferably have a solid consistency.The “term solid” has in this connection the meaning assigned inappropriate pharmacopeas in connection with pharmaceutical preparations.Formulations of the invention may also be of semisolid or viscous liquidconsistency. The terms “semisolid” and “viscous liquid” also have withinthe framework of the present invention the meanings assigned inappropriate pharmacopeas in connection with pharmaceutical preparations.For example, formulations of the invention may be of semisolidconsistency if the contents of lipids and, in particular low-meltinglipids are relatively high. A semisolid and, if desired, also viscousliquid consistency can, as is well known, also be achieved by addingsuitable excipients, in particular low-melting or liquid vehicles.

The present invention therefore also relates to the use of a formulationof the invention where appropriate with the addition of other excipientsas dosage form for the use of at least one active ingredient in the lifescience sector.

Accordingly, formulations of the invention are mainly used in the lifescience sector. This includes, in particular, the pharmaceutical, bothhuman and veterinary medical, sector. In this sense, the formulationsare used as or in drug forms, i.e. the formulations of the inventionhave expedient forms appropriate for pharmaceutical practice, ifnecessary together with other excipients. Analogous statements apply tothe cosmetic sector and adjoining areas such as crop protection, thefoodstuffs sector and the like. Reference is made here inclusively to ause as or in dosage forms, where the term “dosage form” means aformulation shaped with a view to the use.

Thus, the term “drug form” refers to any dosage form for administrationof active ingredients to an organism, preferably to mammals, inparticular humans, and also an agricultural or domestic animals.

Conventional dosage forms include, in particular, drug forms such as (inalphabetical sequence) emulsions and microemulsions, granules, capsules,pellets, powders, suspensions, suppositories, tablets, especially coatedtablets, and analogous dosage forms for use in other life sciencesectors.

Emulsions and microemulsions may be of the oil-in-water or water-in-oiltype and contain the formulations of the invention as disperse ordispersing phase. These emulsions or mieroemulsions may be stabilized bythe presence of emulsifiers known to be used for this purpose. Oneadvantage of formulations of the invention is, however, usually onlysmall amounts of emulsifier are added and, in a particular embodiment ofthe present invention, it is possible to dispense with addition ofemulsifiers, in particular O/W emulsifiers with HLB values over 10 and,in particular, over 15.

Granules consist of solid grains of formulations of the invention, eachgrain representing an agglomerate of powder particles. Granules arepreferably intended for oral use as drug form. The user can be offeredsingle-dose preparations, for example granules packed in a small bag(sachet), a paper bag or a small bottle, or multidose preparations whichrequire appropriate dimensions. However, in many cases, such granules donot represent the actual drug form, but are intermediates in themanufacture of particular drug forms, for example tablet granules to becompressed to tablets, capsule granules to be packed into hard gelatincapsules, or instant granules or granules for oral suspension to be putin water before intake.

As capsules, the formulations of the invention are usually packed into ahard shell composed of two pieces fitted together or a soft, one-piece,closed shell, which may vary in shape and size. It is likewise possiblefor formulations of the invention to be encased or enveloped or embeddedin a matrix in suitable polymers, that is to say microcapsules andmicrospherules. Hard and soft capsules consist mainly of gelatin, whilethe latter have a suitable content of plasticizing substances such asglycerol or sorbitol. Hard gelatin capsules are used to receiveformulations of the invention which have a solid consistency, forexample granules, powder or pellets. Soft gelatin capsules areparticularly suitable for formulations with a semisolid consistency and,if required, also viscous liquid consistency.

Pellets are granules of formulations of the invention in the particlesize range from about 0.5 to 2 mm in diameter. Both with a narrowparticle size distribution, preferably from 0.8 to 1.2 mm, and with anessentially round shape, are preferred.

In semisolid preparations, formulations of the invention are taken up ina suitable vehicle. Appropriate bases are known to the pharmaceuticaltechnologist.

Suppositories are solid preparations for rectal, vaginal or urethraladministration. In order to be appropriate for the administration route,formulations of the invention in these drug forms are usually taken upin suitable vehicles, for example in fats which melt at bodytemperature, such as hard fat, macrogols, i.e. polyethylene glycols withmolecular weights of 1 000 to 3 000 in various proportions, glycerolgelatin and the like.

Tablets are solid preparations in particular for oral use. The meaningof oral within the framework of the present invention is, in particular,that of the term “peroral”, i.e. tablets for absorption or action of theactive ingredient in the gastrointestinal tract. Particular embodimentsare coated tablets, layered tablets, laminated tablets, tablets withmodified release of active ingredient, matrix tablets, effervescenttablets, chewable tablets or pills. The formulations of the inventionusually comprise at least a part of the necessary tablet excipients,such as binders, fillers, glidants and lubricants, and disintegrants.Tablets of formulations of the invention may also if necessary compriseother suitable excipients. Mention should be made in this connection ofexcipients which assist tableting, for example lubricants and glidants,for example those mentioned above, with preference for magensiumstearate in particular for facilitating compaction.

Coated tablets additionally comprise suitable coating materials, forexample film coating agents with coating aids, especially thosementioned below. Coated tablets include, in particular, sugar-coatedtablets and film-coated tablets.

Powders are finely dispersed solids of formulations of the inventionwith particle sizes usually of less than 1 mm. The above statementsabout granules apply correspondingly.

Preference is given according to the invention to capsules packed withcomminuted granules, powders or pellets of formulations of theinvention, instant granules and granules for oral suspension composed offormulations of the invention with addition of masking flavors, and, inparticular, tablets.

The drug forms of the invention are usually packed in a suitable form.Pushout packs made of plastic and/or metal for solid drug forms arefrequently used.

The present invention also relates to a process for producing aformulation of the invention by mixing components i), ii), iii) and,where appropriate, iv) to form a plastic mixture. Thus, to form theplastic mixture, at least two measures are necessary, on the one handthe mixing of the components forming the mixture, and on the other handthe plastication thereof, i.e. the conversion thereof into the plasticstate. These measures may take place for one or more components orportions of components successively, intermeshingly, alternately or inanother way. Accordingly, it is possible in principle fbr the conversioninto the plastic state to take place concurrently during a mixingprocess, or for the mixture first to be mixed and then to be convertedinto the plastic state. A plurality of plastic mixtures differing incomposition may be formed during a process and are mixed together and/orwith other components or portions of components. For example, a premixof a portion of the components can be granulated to form a plasticmixture, and the granules can then be converted, with the addition ofother components, into another plastic mixture whose composition maycorrespond to that of the formulation. It is also possible for all thecomponents first to be combined and then either converted into theplastic state at the same time of the mixing or first mixed and thenconverted into the plastic state.

The formation of a plastic mixture can take place by melting or—withadditional input of mechanical energy, e.g. by kneading, mixing orhomogenizing—melts below the melting point of the mixture. The plasticmixture is preferably formed at temperatures below 220° C. The formationof the plastic mixture usually does not take place by one or morecomponents being converted into a paste or partially dissolved withliquids or solvents, but takes place mainly or exclusively by thermal orthermal/mechanical action on the component(s), i.e. by thermalplastication. The plastic mixture is preferably formed by extrusion,particularly preferably by melt extrusion. The plastication processsteps can be carried out in a manner known per se, for example asdescribed in EP-A-0 240 904, EP-A-0 337 256, EP-A-0358 108, WO 97/15290and WO 97/15291. The contents of these publications and, in particular,the statements about melt extrusion present therein are incorporatedherein by reference.

It should be possible to convert the binder component into a plasticstate in the complete mixture of all the components in the range from 30to 200° C., preferably 40 to 170° C. The glass transition temperature ofthe mixture should therefore be below 220° C., preferably below 180° C.If necessary, it is reduced by conventional, pharmacologicallyacceptable plasticizing excipients.

Examples of such plasticizers are:

organic, preferably involatile compounds, such as, for example,C₇-C₃₀-alkanols, ethylene glycol, propylene glycol, glycerol,trimethylolpropane, triethylene glycol, butandiols, pentanols such aspentaerythritol and hexanols, polyalkylene glycols, preferably having amolecular weight of from 200 to 1 000, such as, for example,polyethylene glycols, polypropylene glycols and polyethylene/propyleneglycols, silicones, aromatic carboxylic esters (e.g. dialkyl phthalates,trimellitic esters, benzoic esters, terephthalic esters) or aliphaticdicarboxylic esters e.g. dialkyl adipates, sebacic esters, azelaicesters, citric and tartaric esters), fatty acid esters such as glycerolmono-, di- or triacetate or sodium diethyl sulfosuccinate. Theconcentration of plasticizer is, where present, generally 0.5 to 30,preferably 0.5 to 10, % by weight based on the total weight of polymerand plasticizer.

The amount of plasticizer advantageously does not exceed 30% by weightbased on the total weight of binder and plasticizer so that—in the areaof solid forms—storage-stable formulations and drug forms showing nocold flow are formed. It is usually unnecessary to add a plasticizer forthe purpose of plastication because the lipid component presentaccording to the invention has plasticizing properties.

The process of the invention can advantageously be carried out attemperatures below 200° C. and preferably below 170° C., but above roomtemperature (25° C.), preferably above 40° C. The process is carried outin particular in a temperature range extending 40° C., preferably 30°C., and particularly preferably 20° C., upward or downward from thesoftening point of the mixture of the components.

In certain cases it may be advantageous to add components or portions ofcomponents as solution or suspension in a solvent. Particularlyexpedient ones are low molecular weight volatile solvents, e.g. water,C₁-C₆-monoalcohols and ethers thereof, esters of C₁-C₆-monoalkanols withC₁-C₆-carboxylic acids, alkanes. Another solvent which can be used isliquid CO₂. Water-soluble active ingredients can be employed as aqueoussolution or, preferably, be taken up in an aqueous solution ordispersion of the binder component or a portion thereof. Correspondingstatements apply to active ingredients which are soluble in one of thesolvents mentioned, if the liquid form of the components used is basedon an organic solvent. The components to be employed according to theinvention may contain small amounts of solvent, e.g. because ofhygroscopicity, trapped solvent or water of crystallization. The totalsolvent content of the plastic mixture is preferably less than 15%, inparticular less than 10%, and particularly preferably less than 5%. Theplastic mixture is preferably formed without the addition of a solvent,i.e. in particular by solvent-free melt extrusion.

The components, i.e. active ingredient, lipid and binder and, whereappropriate, other excipients, can first be mixed and then be convertedinto the plastic state and homogenized. However, it has provedadvantageous, especially on use of sensitive active ingredients, firstto convert at least part of the binder component and at least part ofthe lipid component, where appropriate together with other excipients,into the plastic state. This can be done by operating the apparatusessuch as stirred vessels, agitators, solids mixers etc. alternately.Sensitive active ingredients can then be mixed in (homogenized),preferably in “intensive mixers” in plastic phase with very smallresidence times. The active ingredient(s) may be employed as such, i.e.in solid, semisolid or liquid form, or as solution, suspension ordispersion.

In particular embodiments of the process of the invention, it may beadvantageous initially to form a plastic mixture of binder and activeingredient and, where appropriate, excipients and to add the lipid tothis mixture. This procedure may be advantageous in particular when theactive ingredient has plasticizer-like properties, and the reduction inthe overall process temperature achievable thereby is desirable.

In particular embodiments of the process of the invention it may beadvantageous for the active ingredient and lipid first to be mixed andthen to be added to the plasticated binder. This procedure may beadvantageous in particular when active ingredient and/or lipid arethermally unstable.

The plastication, melting and/or mixing takes place in an apparatususual for this purpose. Extruders or heatable containers with agitator,e.g. kneaders (like those of the type mentioned hereinafter) areparticularly suitable.

It is also possible to use as mixing apparatus those apparatuses whichare employed for mixing in plastics technology. Suitable apparatuses aredescribed, for example, in “Mischen beim Herstellen und Verarbeiten vonKunststoffen”, H. Pahl, VDI-Verlag, 1986. Particularly suitable mixingapparatuses are extruders and dynamic and static mixers, and stirredvessels, single-shaft stirrers with stripper mechanisms, especiallypaste mixers, multishaft stirrers, especially PDSM mixers, solids mixersand, preferably mixer/kneader reactors (e.g. ORP, CRP, AP, DTB from Listor Reactotherm from Krauss-Maffei or Ko-Kneader from Buss), troughmixers or internal mixers or rotor/stator systems (e.g. Dispax fromIKA).

In the case of sensitive active ingredients it is preferable first forthe binder component and the lipid component to be converted into theplastic state, e.g. in an extruder, and then for the active ingredientto be admixed in a mixer/kneader reactor. On the other hand, with lesssensitive active ingredients, a rotor/stator system can be employed forvigorously dispersing the active ingredient.

The process steps of mixing and plastication, that is to say inparticular the melting, can be carried out in the same apparatus or intwo or more apparatuses operating separately from one another. Thepreparation of a premix can be carried out in one of the mixingapparatuses described above and normally used in particular forgranulation. Such a premix can then be fed directly for example into anextruder, and then be extruded where appropriate with the addition ofother components.

It is possible in the process of the invention to employ as extruderssingle screw machines, intermeshing screw machines or else multiscrewextruders, especially twin screw extruders, corotating orcounter-rotating and, where appropriate, equipped with kneading disks.If it is necessary in the extrusion to evaporate a solvent, theextruders are generally equipped with an evaporating section. Examplesof extruders which can be used are those of the ZSK series from Werner &Pfleiderer.

The mixing apparatus is charged continuously or batchwise, depending onits design, in a conventional way. Powdered components can be introducedin a free feed, e.g. via a weigh feeder. Plastic compositions can be fedin directly from an extruder or via a gear pump, which is particularlyadvantageous if the viscosities and pressures are high. Liquid media canbe metered in by a suitable pump unit.

The lipid component—as described above—be incorporated continuously orbatchwise into the formulation. Thus, at least part of the bindercomponent (matrix) can first be used as support for at least part of thelipid component, and then be formulated according to the invention aspremix to form a plastic mixture, possibly with addition of otheringredients, preferably by extrusion. Continuous addition of at leastpart of the lipid component to a plastic mixture is preferred. This isparticularly preferred when the lipids to be used according to theinvention can be processed in semisolid or liquid form. Accordingly, thelipids described above and having relatively low melting points are alsopreferred for technical reasons in the process, and of these in turnpreference is given to those which at room temperature, i.e. about 20 to30° C., are of semisolid (waxy), and preferably of liquid (oil)consistency. It is preferred for these to be metered directly into themixing apparatus, in particular an extruder. This may save a granulationstep to be carried out separately. It is particularly advantageous toincorporate the lipid-like active ingredients, that is to say inparticular the essential oils, continuously into the appropriate bindermatrix, preferably in an extruder, feeding the oil continuously into anextruder carrying the binder mixture, and extruding the resultingformulation as plastic mixture.

The mixture which has been obtained by mixing and converting the bindercomponent, the active ingredient component, the lipid component and,where appropriate, other excipients into the plastic state is pasty, ofhigh viscosity or low viscosity (thermoplastic) and can therefore alsobe extruded. The glass transition temperature of the mixture isadvantageously below the decomposition temperature of all the componentspresent in the mixture.

The formulation of the invention is suitable as plastic mixture—whereappropriate after cooling or solidification—in particular as extrudate,for all conventional processes for manufacturing conventional dosageforms.

The present invention also relates to a process for producing dosageforms of formulations of the invention, where the formulation can beproduced by the above process, and the formulation is converted into therequired dosage form where appropriate with the addition of otherexcipients. This can be done by using shaping process measures such asshaping the plastic mixture, in particular by extrusion or meltextrusion, and shaping the plastic mixture, in particular theextrudate—where appropriate after cooling or solidification—for exampleby granulation, grinding, compression, casting, injection molding,tableting under pressure, tableting under pressure with heat. It is alsopossible to convert a formulation into a desired dosage form byintroducing it into suitable vehicles. It is thus also possible toprocess solid formulations into semisolid or liquid formulations throughthe addition of suitable vehicles.

A large number of, in particular, solid dosage forms can be manufacturedin this way. For example, powders or granules can be produced bygrinding or chopping the solidified or at least partly solidifiedplastic mixture, and can be either used directly or, where appropriatewith addition of conventional excipients, further processed to the abovedosage forms, especially to tablets.

Dosage forms are preferably shaped before solidification of the plasticmixture and result in a form which can be employed where appropriateafter coating in a conventional way.

The shaping to the dosage form before solidification can take place in avariety of ways depending on the viscosity of the plastic mixture, forexample by casting, injection molding, compression, nipping orcalendering. This is done by conveying the plastic mixture describedabove in the process according to the invention to one or more shapingsteps. The conveying can take place by pressing, pumping, e.g. with gearpumps, or, preferably, with an extruder.

The plastic mixture is particularly preferably formed in one or more,preferably one, extruder and conveyed by the latter or a downstreamextruder to the shaping steps. It has proved to be advantageous in manycases to extrude on a downward incline and/or where appropriate providea guide channel for transporting the extrudate, in order to ensure safetransport and prevent rupture of the extrudate.

It may also be advantageous, depending on the number and compatibilityof the active ingredients to be employed, to employ multilayerextrudates, for example coextrudates, as described in WO 96/19963, inthe process of the invention.

Multilayer solid dosage and, in particular, drug forms can be producedin particular by coextrusion, in which case a plurality of mixtures ofone or more of the components described above are conveyed together intoan extrusion die so that the required layer structure results. Differentbinders are preferably used for different layers.

Multilayer dosage and, in particular, drug forms preferably comprise twoor three layers. They may be in open or closed form, in particular asopen or closed multilayer tablets.

If the shaping takes place by coextrusion, the mixtures from theindividual extruders or other units are fed into a common coextrusiondie and extruded. The shape of the coextrusion dies depends on therequired drug form. Examples of suitable dies are those with a flatorifice, called slit dies, and dies with an annular orifice. The designof the die depends on the formulation base used and, in particular, thebinder component and the desired shape.

The first shaping step advantageously takes place when the extrudateemerges from the extruder through suitably shaped dies, draw plates orother orifices, for example through a baker plate, a circular die or aslit die. This usually results in a continuous extrudate, preferablywith a constant cross section, for example in the form of a ribbon or ofa strand, preferably with a circular, oval, rounded or flat and broadcross section.

Suitable downstream shaping steps for extrudates are, for example, coldcut, that is to say the cutting or chopping of the extrudate after atleast partial solidification, hot cut, that is to say the cutting orchopping of the extrudate while still in the plastic form, or pinchingoff the still plastic extrudate in a nip device. It is possible with hotor cold cut to obtain, for example, granules (hot or cold granulation)or pellets. Hot granulation usually leads to dosage forms (pellets) witha diameter of from 0.5 to 3 mm, while cold granulation normally leads tocylindrical products with a length to diameter ratio of from 1 to 10 anda diameter of from 0.5 to 10 mm. It is possible in this way to producemonolayer but also, on use of coextrusion, open or closed multilayerdosage forms, for example oblong tablets, pastilles and pellets. Thedosage forms can be provided with a coating by conventional methods in adownstream process step. Suitable materials for film coatings are thepolymers mentioned as polymeric binders, in particular polyacrylatessuch as the EudragitR types, cellulose esters such as thehydroxypropylcellulose phthalates, and cellulose ethers such asethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose,and gelatin. Further shaping steps may also follow, such as, forexample, rounding off the pellets obtained by hot or cold cut usingrounding-off devices as described in DE-A-196 29 753.

It is particularly preferred for all the shaping steps to be carried outon the still plastic mixture or still plastic extrudate. Besides hotcut, where appropriate with subsequent rounding off, a particularlysuitable process is one in which the plastic mixture is shaped to thedosage form in a molding calender. This is done by conveying a stillplastic mixture or a still plastic extrudate to a suitable moldingcalender. Suitable molding calenders usually having molding rolls and/orbelts for the shaping, with at least one of the molding rolls and/or atleast one of the belts having depressions to receive and shape theplastic mixture. It is preferred to use a molding calender withcounter-rotating molding rolls, with at least one of the molding rollshaving on its surface depressions to receive and shape the plasticmixture. Suitable molding calenders and devices containing molding rollsare generally disclosed for example in EP-A-0 240 904, EP-A-0 240 906and WO 96/19962, and suitable belts and devices containing belts aregenerally disclosed for example in EP-A-0 358 105, which are expresslyincorporated herein by reference.

The shaping of the still plastic mixture or still plastic extrudatepreferably takes place at temperatures below 220° C., particularlypreferably below 180° C. and very particularly preferably below 150° C.,such as, for example, in the temperature ranges necessary to form theplastic mixture or at lower temperatures. If the shaping takes place atlower temperatures, it advantageously takes place at from 5 to 70° C.,preferably 10 to 50° C. and particularly preferably 15 to 40° C. belowthe highest temperature reached on formation of the plastic mixture, butpreferably above the solidification temperature of the plastic mixture.

The production according to the invention of the formulations andpreparation of the dosage forms can be carried out wholly or partlyunder sterile operating conditions, for example in cleanrooms and withuse of sterilized equipment such as, for example, weighers, mixers,extruders and shaping machines, such as calenders, nip devices andchoppers. It is possible either for the starting materials to beintroduced into the process in sterilized form, where appropriate withthe addition of suitable antibacterial and/or antiviral excipients,and/or for the process conditions, especially the temperature, to bechosen such that sterile formulations or drug forms are obtained. Theresulting sterile dosage forms can then be packaged directly, likewiseunder sterile conditions, for example by blister packing or sealing. Theshaping and the packaging may also be carried out at the same time, inparticular when the shaping of the plastic mixture by calendering iscarried out by molding rolls. This is done by introducing, in additionto the plastic mixture, materials in the form of sheets between the meltand the molding roll in each case, whereby it is possible to achieve atthe same time as the shaping of the plastic mixture to dosage forms anenveloping and/or a packaging of the dosage form, as described inWO-96/19963, which is incorporated herein by reference.

The present invention further relates to the use of a formulation baseof the invention in the use of at least one active ingredient in thelife science sector, that is to say, in particular, in the drugs,cosmetics, crop protection, foodstuffs, and washing, cleaning andhygiene sectors.

The purpose of this use is, in particular, to improve the effect of theactive ingredient component. Thus, this use comprises in particular aprocess for improving the effect of the active ingredient component onuse of at least one active ingredient in the life science sector, withuse of a formulation base of the invention. This entails introducing atleast one active ingredient into this formulation base, preferably usingone of the processes described above. In particular, the binder matrixof the formulation base serves to receive at least one lipid in theproduction of a solid formulation of the invention to improve the effectof the active ingredient component.

The binder matrix is formed by the binder component described above orat least a part thereof. At least one lipid, which is a constituent ofthe lipid component described above and/or of the active ingredientcomponent, is taken up in this binder matrix. It is particularlypreferred for the taking up to result in an essentially moleculardispersion of lipid in the binder matrix. A homogeneous distribution oflipid in the matrix is advantageous, especially in relation to theactive ingredient-promoting properties of the lipid. These advantagescan be achieved even without the active ingredient being in a moleculardispersion. Lipids which can be used to improve the pharmacologicaleffect of an active ingredient are known to the skilled worker, interalia as absorption promoters. He is able to select at least part of thelipid component for example from among them. In addition, reference ismade to the statements above in connection with the description of thelipid component.

The use according to the invention is particularly advantageous wheneveractive ingredients are to be used in such a way that an activeingredient-promoting effect may occur on simultaneous administration oflipids. This relates in the pharmacy sector in particular to routes ofadministration which include the gastrointestinal tract, that is to say,in particular, enteral, especially rectal and, preferably, oraladministration. The use according to the invention is very particularlyadvantageous when an active pharmaceutical ingredient to be administeredcan be used only inadequately by this route without suitable measuressuch as the addition of at least one lipid.

The invention also relates to the use of a formulation of the inventionwhere appropriate with the addition of other excipients as dosage formin the life science sector.

The dosage forms include, in particular, the aforementioned drug forms.Corresponding dosage forms for cosmetic use, for plant treatment, forfood technology, including human and animal food technology, and otheradjoining areas can be manufactured taking account of expedient,use-specific embodiments. The use according to the invention is directedin particular at human and veterinary medical treatment, cosmetictreatment, crop protection, the supplementation of human and animalfoods with active ingredients, and the inclusion of active ingredientsin washing, cleaning and hygiene products.

A particular use relates to the addition of formulations of theinvention to hygiene products, especially diapers for babies. Theformulations particularly used within the framework of this use arethose based on lipid-like active ingredients. It is thus possible to usesolid or semisolid formulations with odorants or other hydrophobicactive ingredients, e.g. substances with antimicrobial activity,especially the aforementioned essential oils. When these formulationscome into contact with body fluids they form an emulsion whose largesurface area allows odorants in particular to act efficiently.

Drug forms of the invention, and thus an effective amount of activeingredient, are administered to the individual to be treated, preferablya mammal, in particular a human, and also an agricultural or domesticanimal. Whether such a treatment is indicated and what form it is totake depends on the individual case and is subject to medical assessment(diagnosis) which includes the signs, symptoms and/or dysfunctions whichare present, the risks of developing certain signs, symptoms and/ordysfunctions, and other factors. The drug forms of the invention areusually administered one or more times a day together or alternatelywith other products in such a way that an individual to be treatedreceives a daily dose in an amount which makes therapy possible.

The formulations of the invention represent self-emulsifying systems.Emulsions are formed when the formulations come into contact withaqueous media. Accordingly, the present invention also relates to aprocess for producing emulsions. These emulsions are usually stable,especially under the conditions of use of the formulations of theinvention. Thus, the formulations usually form stable emulsions even attemperatures below 90° C. Preferred temperature ranges for the formationof stable emulsions are from 5 to 60° C. and, in particular from 10 to40° C. It is advantageous for these to be fine-particle emulsions with apredominant content of particles with diameters of less than 100 μm,preferably of less than 50 μm and, in particular, of less than 20 μm.Formulations which form emulsions on contact with aqueous medium and inwhich at least 50% of the particle diameters are in a range from 100 to20 000 nm, preferably from 10 to 5 000 nm and, in particular, from 300to 2 000 nm are preferred embodiments.

Under the conditions of use, the emulsions normally form spontaneously.In particular, negligible input of mechanical energy, e.g. stirringand/or shear energy, is necessary. Thus, formulations of the inventioncan initially be produced in the absence of solvents. The formation ofthe emulsion then takes place, depending on the use, when contact ismade with an aqueous medium, in the drug form sector beforeadministration by preparing an appropriate dosage form or afteradministration on contact with a suitable body fluid.

The formation of fine-particle emulsions is assisted especially throughthe formulations of the invention being in the state of a moleculardispersion and in particular a solid solution.

Thus, formulation bases of the invention are particularly preferred whenlipid emulsions are preferred for the use of active ingredients. Thisparticularly relates to active ingredients of low solubility; activeingredients which, although readily soluble, display an only inadequateeffect on enteral administration; and/or active ingredients which causelocal irritation and/or other unwanted side effects. This applies justas much to topical administration forms such as, for example, lotions,creams and ointments as to parenteral administration forms such as, forexample, solutions for injection, and oral administration forms, e.g.drinkable solutions and solid dosage forms, for example tablets andcapsules.

The use of the aforementioned binders in particular has its effect inthe formation of the emulsions. These binders and, in particular, thepolymeric binders are able to act as solubilizers and thus assume thefunction of emulsifiers as in relation to the emulsification of thelipids. A further aspect of the present invention is therefore the useof the binder component for emulsifying the lipid component.

The present invention is now to be illustrated, but not restricted, bymeans of the following examples.

EXAMPLE 1

A mixture of equal parts by weight of hydroxypropylcellulose (Klucel EF,Aqualon) and oleic acid was processed at 120° C. in a measuring kneader(Rheomix, from Haake) to a homogeneous, rubber-like melt. Coolingresulted in a transparent solid mass which dissolved in water to form anemulsion.

EXAMPLE 2

The experiment took place in analogy to example 1, but with a mixture of60% by weight of Kollidon VA-64 (BASF) and 40% by weight of oleic acidat a temperature of 100° C. over 5 minutes. A clear, low-viscosity,transparent melt was obtained and was, after cooling to room temperature(and even after storage at room temperature for 12 months), clearlytransparent and still plastically deformable. The cooled melt dissolvedreadily to form an emulsion in water. The size of the emulsion dropletsin this preparation was measured using a Mastersizer instrument (fromMalvern, UK). 90% of the particles had sizes below 35 μm, and 50% of theparticles were smaller than 2 μm.

EXAMPLE 3

The experiment took place in analogy to example 2, with a mixture of 72%by weight of Kollidon VA-64 (BASF) and 28% by weight of oleic acid. Thecooled melt was likewise transparent but less readily plasticallydeformable than in Example 2. The cooled melt dissolved readily in waterto form an emulsion. The size of the emulsion droplets in thispreparation was measured using a Mastersizer instrument (from Malvern,UK). 90% of the particles had sizes below 4 μm, and 50% of the particleswere smaller than 0.7 μm.

EXAMPLE 4

The experiment took place as in example 3, but with a mixture of 64% byweight of Kollidon VA-64 (BASE), 16% by weight of oleic acid and 20% byweight of dextran 118° C. The resulting whiteish melt became solid aftercooling and it dissolved quite rapidly in 0.1 M HCl to form an emulsion.

EXAMPLE 5

The experiment took place as in example 4, but with a mixture consistingof 70% by weight of hydroxypropylcellulose (Klucel EF, Aqualon), 10% byweight of oleic acid and 20% by weight of dextran at 120° C. Theresulting white melt became solid after cooling and dissolved in waterto form an emulsion, but more slowly than in the case of example 4.

EXAMPLE 6

The experiment took place as in example 5, but with a mixture consistingof 40% by weight of hydroxypropylcellulose (Klucel EF, Aqualon), 40% byweight of stearic acid and 20% by weight of dextran at 120° C. Theresulting white melt was, after cooling and grinding, relatively easilydispersible in water to form an emulsion.

EXAMPLE 7

The experiment took place as in example 1, but with a mixture consistingof 70% by weight of hydroxypropylcellulose (Klucel EF, Aqualon) and 30%by weight of stearic acid at 110° C. A clear, rubber-like melt formedand, on cooling, formed a white solid.

EXAMPLE 8

1 part by weight of oleic acid was added to 7 parts by weight ofKollidon VA-64 (BASF) with gentle kneading. Kneading for a few minutesresulted, with slight evolution of heat, in homogeneous granules whichwere mixed with 2 parts by weight of the active ingredient esuprone. 1%by weight of highly disperse silica (Aerosil 200) was then added to thisgranular mixture, and this mixture was then metered via a weigh feederinto a twin screw extruder (16 mm screw diameter) and extruded at atemperature of 110° C. The resulting clear melt could, after cooling, bedissolved in water to form an emulsion.

EXAMPLE 9

The experiment was carried out in analogy to example 8 but with 2 partsby weight of paracetamol which had been kneaded with a previouslygranulated mixture of 7 parts by weight of Kollidon VA-64 (BASF) and 1part by weight of oleic acid. 1% by weight of Aerosil 200 was likewiseadded to the overall mixture while mixing before the extrusion. Theextrusion took place at a temperature of 125° C., and the cooled meltdissolved in water to form a fine-particle emulsion.

EXAMPLE 10

The experiment took place as in example 8 but with with 2 parts byweight of paracetamol and a granular mixture of 6.125 parts by weight ofKollidon VA-64 (BASF), 0.875 parts by weight of oleic acid and 1 part byweight of stearyl alcohol. 1% by weight of Aerosil 200 was likewiseadded to the overall mixture while mixing before the extrusion. Theextrusion took place at a temperature of 120° C., and the cooled meltdissolved in water to form a fine-particle emulsion.

Examples 11 to 13 which follow illustrate formulations of the inventionwith lipid-like active ingredients, in these cases orange oil asessential oil. The mixtures were processed in a Werner & PfleidererZSK30 twin screw extruder with a throughput of 2.7 kg/hour. The shapingof the still plastic extrudate took place as described in EP-A 240 906.The metering in from the side took place with an HPLC pump with apumping rate of 300 g/h in section 2.

EXAMPLE 11

2% by weight of a PVP homopolymer with a K value of 30 (Kollidon 30),70% by weight of isomalt, 18% by weight of maltodextrin with DE 15(C-Pur 01915, from Cerestar) were mixed in a twin screw extruder. 10% byweight of orange oil were metered in from the side and continuouslyincorporated into the matrix. After extrusion, the mixture was convertedinto pellets about 1 mm in size by hot cut. The temperature in theindividual sections was 39° C., 57° C., 110° C., 89° C. and 89° C., andthat of the die was 101° C.

EXAMPLE 12

2% by weight of hydroxypropylcellulose with a weight average molecularweight of about 80 000 (Klucel EF), 70% by weight of isomalt, 18% byweight of maltodextrin with DE 15 (C-Pur 01915, from Cerestar) weremixed in a twin screw extruder. 10% by weight of orange oil were meteredin from the side and continuously incorporated into the matrix. Afterextrusion, the mixture was converted into pellets about 1 mm in size byhot cut. The temperature in the sections was 61° C., 84° C., 120° C.,111° C. and 100° C., and that of the die was 111° C.

EXAMPLE 13

2% by weight of a PVP homopolymer with a K value of 30 (Kollidon 30),53% by weight of isomalt, 35% by weight of maltodextrin with DE 15(C-Pur 01915, from Cerestar) were mixed in a twin screw extruder. 10% byweight of orange oil were metered in from the side and continuouslyincorporated into the matrix. After extrusion, the mixture was convertedinto pellets about 1 mm in size by hot cut. The temperature in thesections was 52° C., 64° C., 110° C., 92° C. and 91° C., and that of thedie was 104° C.

1. A solid, self-emulsifying formulation comprising: i) an activepharmaceutical ingredient, ii) 6 to 60% by weight of a lipid component,wherein said lipid component has an HLB of not exceeding 12 and amelting point of not exceeding 50° C., iii) 30 to 90% by weight of abinder component, wherein said binder component comprises a binderselected from polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetatecopolymer, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, cellulosephthalate or (meth)acrylic resin, wherein said formulation isessentially free of lipid and active ingredient crystals, and comprisesa molecular dispersion of said lipid component in said binder component.2. The formulation of claim 1, wherein said formulation is capable ofspontaneously forming an emulsion upon contact with an aqueous medium.3. The formulation of claim 1, wherein said formulation is capable ofspontaneously forming an emulsion upon contact with water.
 4. Theformulation of claim 1, wherein said formulation is essentiallyamorphous.
 5. The formulation of claim 1, wherein said binder has a Kvalue between 10 and
 100. 6. The formulation of claim 1, wherein saidbinder has a K value between 15 and
 80. 7. The formulation of claim 1,wherein said binder is a vinylpyrrolidone/vinyl acetate copolymer with avinylpyrrolidone:vinyl acetate ratio of 60:40.
 8. The formulation ofclaim 1, wherein said lipid component is of liquid at room temperature.9. The formulation of claim 1, wherein said lipid component has an HLBof not exceeding
 8. 10. The formulation of claim 1, wherein said lipidcomponent has an HLB of not exceeding
 5. 11. The formulation of claim 1,wherein said lipid component has a melting point of not exceeding 40° C.12. The formulation of claim 1, wherein said lipid component has amelting point of not exceeding 30° C.
 13. The formulation of claim 1,wherein said formulation is a tablet.
 14. The formulation of claim 1,wherein said formulation is not an emulsion or microemulsion.
 15. Theformulation of claim 1, wherein said formulation comprises 40 to 80% byweight of said binder component, and the content of the lipid componentbased on the binder component does not exceed 25% by weight.
 16. Theformulation of claim 15, wherein said formulation is essentiallyamorphous.
 17. The formulation of claim 16, wherein said lipid componentis of liquid at room temperature.
 18. The formulation of claim 16,wherein said lipid component has a melting point of not exceeding 40° C.19. The formulation of claim 16, wherein said lipid component has amelting point of not exceeding 30° C.
 20. The formulation of claim 17,wherein said binder component has a K value between 15 and
 80. 21. Theformulation of claim 17, wherein said binder component ispolyvinylpyrrolidone, vinylpyrrolidone copolymer with vinyl acetate,hydroxypropylcellulose, hydroxypropylmethylcellulose, orhydroxypropylmethylcellulose phthalate.
 22. The formulation of claim 17,wherein said binder component is a vinylpyrrolidone/vinyl acetatecopolymer with a vinylpyrrolidone:vinyl acetate ratio of 60:40.
 23. Theformulation of claim 22, wherein said formulation is a tablet.
 24. Theformulation of claim 23, wherein said formulation is capable ofspontaneously forming an emulsion upon contact with water.
 25. Theformulation of claim 23, wherein said active pharmaceutical ingredienthas low solubility and requires at least 10,000 parts of water todissolve one part of said active pharmaceutical ingredient.
 26. Theformulation of claim 23, wherein said lipid component is an ester ofglycerol.
 27. The formulation of claim 21, wherein said formulation is atablet and is capable of spontaneously forming an emulsion upon contactwith water.
 28. The formulation of claim 16, wherein said formulation isprepared by a process comprising: forming a plastic mixture by meltextrusion, said plastic mixture comprising said active ingredient, saidbinder component and said lipid component, and cooling or solidifyingsaid mixture.
 29. The formulation of claim 28, wherein the plasticmixture is formed at a temperature of below 170° C.
 30. The formulationof claim 28, wherein said process further comprises (1) granulating thecooled or solidified mixture and (2) tabletting the granulated mixturewith or without other excipients.